Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity

Xia, Jianguo; Zou, Jin; Peng, Haibo; Stolle, Anne-Sophie; Xie, Ruiqiang; Zhang, Hongjie; Peng, Bo; Mekalanos, John J.; Zheng, Jun

doi:10.1073/pnas.1822026116

Cited by 54 publications

(44 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, colistin might be a good candidate for combinational therapy with β-lactam antibiotics to treat A. baumannii infection. This result is also consistent with our previous studies that targeting bacterial persistence or tolerance could highly enhance the antibiotic treatment [27,57].…”

Section: Discussionsupporting

confidence: 93%

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

Zou¹,

Kou²,

Xie³

et al. 2020

Emerging Microbes & Infections

Self Cite

View full text Add to dashboard Cite

Bacterial persistence is one of the major causes of antibiotic treatment failure and the step stone for antibiotic resistance. However, the mechanism by which persisters arise has not been well understood. Maintaining a dormant state to prevent antibiotics from taking effect is believed to be the fundamental mechanistic basis, and persisters normally maintain an intact cellular structure. Here we examined the morphologies of persisters in Acinetobacter baumannii survived from the treatment by three major classes of antibiotics (i.e. β-lactam, aminoglycoside, and fluoroquinolone) with microcopy and found that a fraction of enlarged spherical bacteria constitutes a major sub-population of bacterial survivors from β-lactam antibiotic treatment, whereas survivors from the treatment of aminoglycoside and fluoroquinolone were less changed morphologically. Further studies showed that these spherical bacteria had completely lost their cell wall structures but could survive without any osmoprotective reagent. The spherical bacteria were not the viable-but-nonculturable cells and they could revive upon the removal of β-lactam antibiotics. Importantly, these non-walled spherical bacteria also persisted during antibiotic therapy in vivo using Galleria mellonella as the infection model. Additionally, the combinational treatment on A. baumannii by β-lactam and membrane-targeting antibiotic significantly enhanced the killing efficacy. Our results indicate that in addition to the dormant, structure intact persisters, the non-wall spherical bacterium is another important type of persister in A. baumannii. The finding suggests that targeting the bacterial cell membrane during β-lactam chemotherapy could enhance therapeutic efficacy on A. baumannii infection, which might also help to reduce the resistance development of A. baumannii.

show abstract

Section: Discussionsupporting

confidence: 93%

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

Zou¹,

Kou²,

Xie³

et al. 2020

Emerging Microbes & Infections

Self Cite

View full text Add to dashboard Cite

show abstract

“…We suspected that the genetically encoded ATP sensor can act as a buffer absorbing some of this ATP flux from a loss of translation, while the luminescence-based assay measures absolute values after the cells are permeabilized. This interpretation is consistent with recent results which show an increase in an alarmone with an ATP precursor after aminoglycoside treatment 41 . Collectively these data suggest that there may be a change in metabolic flux in the system, and are consistent with prior observations of aminoglycoside treated cells, which were found to leak NTPs 6 and increase respiration 18 .…”

Section: Atp Dysregulation Precedes Voltage Induced Bactericidal Killsupporting

confidence: 94%

Membrane voltage dysregulation driven by metabolic dysfunction underlies bactericidal activity of aminoglycosides

Bruni

Kralj

2020

Preprint

View full text Add to dashboard Cite

Aminoglycosides are broad-spectrum antibiotics whose mechanism of bactericidal activity has been under debate. It is widely accepted, however, that membrane voltage potentiates aminoglycoside activity, which is ascribed to voltage dependent drug uptake. In this paper, we measured the single cell response of Escherichia coli treated with aminoglycosides and discovered that the bactericidal action arises not from the downstream effects of voltage dependent drug uptake, but rather directly from dysregulated membrane potential. In the absence of voltage, aminoglycosides are taken into cells and exert bacteriostatic effects by inhibiting translation. However, cell killing was immediate upon re-polarization. The hyperpolarization arose from altered ATP flux, which induced a reversal of the F1Fo-ATPase to hydrolyze ATP and generated the deleterious voltage. Heterologous expression of an ATPase inhibitor from Salmonella completely eliminated bactericidal activity, while loss of the F-ATPase significantly reduced the electrophysiological response to aminoglycosides. Our data support a model of voltage induced death, which could be resolved in real-time at the single cell level, and separates the mechanisms of aminoglycoside bacteriostasis and bactericide in E. coli.

show abstract

“…Studies on the function of Ap 4 A in Escherichia coli have shown that it may be a damage metabolite and a few proteins binding Ap 4 A in these bacteria were identified [178]. Recent studies on the function of Ap 4 A have shown that aminoglycoside antibiotics induced synthesis of Ap 4 A in Escherichia coli and it caused bacterial cell killing by these antibiotics [179]. Lysyl-tRNA synthetase plays a key role in MITF (microphthalmia-associated transcription factor) transcriptional activity via Ap 4 A as an important signaling molecule in mast cells [180,181].…”

Section: Function Of Uncommon Nucleotidesmentioning

confidence: 99%

New Insight into Plant Signaling: Extracellular ATP and Uncommon Nucleotides

Pietrowska‐Borek

Dobrogojski

Sobieszczuk‐Nowicka

et al. 2020

Cells

View full text Add to dashboard Cite

New players in plant signaling are described in detail in this review: extracellular ATP (eATP) and uncommon nucleotides such as dinucleoside polyphosphates (NpnN’s), adenosine 5′-phosphoramidate (NH2-pA), and extracellular NAD+ and NADP+ (eNAD(P)+). Recent molecular, physiological, and biochemical evidence implicating concurrently the signaling role of eATP, NpnN’s, and NH2-pA in plant biology and the mechanistic events in which they are involved are discussed. Numerous studies have shown that they are often universal signaling messengers, which trigger a signaling cascade in similar reactions and processes among different kingdoms. We also present here, not described elsewhere, a working model of the NpnN’ and NH2-pA signaling network in a plant cell where these nucleotides trigger induction of the phenylpropanoid and the isochorismic acid pathways yielding metabolites protecting the plant against various types of stresses. Through these signals, the plant responds to environmental stimuli by intensifying the production of various compounds, such as anthocyanins, lignin, stilbenes, and salicylic acid. Still, more research needs to be performed to identify signaling networks that involve uncommon nucleotides, followed by omic experiments to define network elements and processes that are controlled by these signals.

show abstract

Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity

Cited by 54 publications

References 55 publications

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

Membrane voltage dysregulation driven by metabolic dysfunction underlies bactericidal activity of aminoglycosides

New Insight into Plant Signaling: Extracellular ATP and Uncommon Nucleotides

Contact Info

Product

Resources

About